MLL-rearranged infant ALL remains the most aggressive type of childhood leukemia for which adequate treatment regimens are still lacking (Pieters et al., Lancet 370(9583):240-250, 2007; Pui et al., Lancet 371(9617):1030-1043, 2008). Conventional combination chemotherapy, successfully used to treat older children with ALL without MLL rearrangements, fails in over 50% of the infant MLL-rearranged leukemia cases. Despite recent efforts in the optimization of therapeutic approaches for infants, defined as children below the age of one year, with ALL, the prognosis for the majority of these patients remains dismal.
MLL-rearranged infant leukemia is a malignancy of white blood cells characterized by rearrangement of the mixed lineage leukemia (MLL) gene on chromosome 11q23. Unlike most other recurrent translocations, MLL rearrangements are found in leukemias classified as acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL). MLL-rearranged leukemias often express both myeloid- and lymphoid-associated genes. Approximately 80% of infants with ALL carry leukemia-specific translocations involving the MLL gene.
MLL-rearranged leukemias are distinguishable from other types of leukemias by their unique genome-wide gene expression profiles and leukemia-specific histone modifications (Armstrong et al. Nat Genet 30(1):41-47, 2002; Krivtsov et al. Cancer Cell 14(5):355-368, 2008; Krivtsov & Armstrong, Nat Rev Cancer 7(11):823-833, 2007; Stam et al., Blood 115(14):2835-2844, 2010). As the wild-type MLL gene is normally functioning as an epigenetic regulator through histone methyltransferase activity, abrogation of the normal function of MLL in hematopoietic cells leads to erroneous histone modifications. Apparently, such epigenetic deregulation favors leukemia development (Guenther et al., Genes Dev 22(24):3403-3408, 2008). Recently, it was shown that apart from inappropriate histone modifications, the epigenetic landscape in MLL-rearranged infant ALL cells is further altered by severe aberrant DNA methylation at numerous gene promoters (Stumpel et al., Blood 114(27):5490-5498, 2009). The majority of infants with MLL-rearranged ALL, especially those bearing translocation t(4;11), representing the most common type of MLL-rearrangement among infant ALL patients, suffer from severely hypermethylated leukemias.
The pattern of methylation has recently become an important topic for research. Studies have found that in normal tissue methylation of a gene is mainly localized in the coding region, which is cytosine-phosphate-guanine (CpG) poor. In contrast, the promoter region of the gene is unmethylated despite a high density of CpG islands in the region.
Neoplasia is characterized by “methylation imbalance” where genome-wide hypomethylation is accompanied by localized hypermethylation and an increase in expression of DNA methyltransferase (Chen et al., Nature 395 (6697):89-93, 1998). The overall methylation state in a cell might also be a precipitating factor in carcinogenesis as evidence suggests that genome-wide hypomethylation can lead to chromosome instability and increased mutation rates (Baylin et al., Adv. Cancer Res. 72:141-96, 1998). The methylation state of some genes can be used as a biomarker for tumorigenesis. For instance, hypermethylation of the pi-class glutathione S-transferase gene (GSTP1) appears to be a promising diagnostic indicator of prostate cancer (Nakayama et al., J. Cell. Biochem. 91(3):540-52, 2004).
As treatment of MLL-rearranged infant ALL remains a major challenge, there is a need for compounds and methods for the treatment of the disease.